Graves' disease (GD) accounts for the vast majority of cases of hyperthyroidism in young adults. It is estimated that there are 30,000 women of childbearing age with GD in the United States (US), and that 4,000 to 8,000 women are treated for GD during pregnancy annually. Antithyroid drug (ATD) therapy is the recommended treatment of GD during pregnancy. Based on observations of birth defects (aplasia cutis and choanal atresia) in offspring of mothers treated with MMI during pregnancy, and the absence of such reports related to PTU use, PTU has been recommended as the drug-of-choice for pregnant women with GD. In preliminary studies, in US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) data, we discovered a substantial number of major birth defects in the offspring of women treated with PTU during pregnancy. In our analysis of International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) data, we observed birth defects with PTU (congenital heart defects) and MMI (choanal atresia, omphalocelle) use during pregnancy. In murine models, we observed that PTU exposure during embryogenesis (E7.5 to 10.5) is associated with skull and cardiac defects, whereas we do not observe malformations in embryos of dams treated with MMI or high doses of levo-thyroxine (LT4). These observations suggest that current recommendations for the treatment of GD during pregnancy with ATDs may not be optimal. Considering the above data, we hypothesize that (1) PTU use during pregnancy is associated with a risk of major birth defects. (2) The nature of birth defects associated with hyperthyroidism, PTU and MMI use during pregnancy differ in type and incidence. (3) Hyperthyroidism itself may contribute to birth defects during pregnancy. (4) There is a risk of liver injury to pregnant mothers during pregnancy associated with PTU use. To test these hypotheses, two specific aims are proposed: Specific Aim 1: Assess the risks of ATD treatment during pregnancy on mother and fetus. Cohort studies will be performed using large clinical databases, including those of Marketscan (>1.2 million pregnancies) and Kaiser Permanente Northern California (KPNC; (>300,000 pregnancies). Databases will be analyzed to assess the prevalence of GD in pregnancy, ATD treatment use in pregnant women with GD, co-morbid conditions (i.e., liver disease) associated with GD and ATD use in pregnancy, and birth defects and other co-morbid conditions in infants born to mothers with GD and treated with ATDs. Specific Aim 2: Assess teratogenic potential of PTU and MMI. To complement human cohort studies, we will perform basic teratogenicity studies to assess the birth defect risks of PTU and MMI. We will examine effects on fetal viability, growth and morphology, as related to drug dose. We will define periods of vulnerability of the embryo to affects of PTU and MMI. We will examine the contribution of the hyperthyroid state to birth defects. We will use methods and a testing laboratory that satisfies requirements of the FDA. These studies will involve collaborative efforts with Dr. James Korelitz (Westat), who is an expert in database interrogation; Dr. Joan C. Lo, M.D. (Kaiser Permanente), who is an expert in endocrinology and database analysis; Dr. Alan Hoberman (Charles River Laboratory), who is an expert in teratogenicity testing and Dr. Scott Rivkees (Yale University) who is an expert in developmental biology and thyroid disorders. It is anticipated that these studies will provide new insights into the risks involved with ATD treatment of GD during pregnancy. When completed, we anticipate that these studies will provide needed epidemiology and basic-teratology data about the relative risks of PTU, MMI, and hyperthyroidism to mother and fetus.